Substituted acetamide derivatives, process for their preparation and antiulcer drug containing same

ABSTRACT

A substituted acetamide derivative of general formula (I): ##STR1## [in which Y represents as piperidino group, 1-pyrrolidinyl group or 3-hydroxy-1-pyrrolidinyl group, and Z represents a group selected from the group consisting of (a) to (e): (a) a cyano group, ##STR2## its salts, its cyclodextrin inclusion compounds and antiulcer drugs comprising them as their active ingredient are disclosed. Compounds (I) have excellent antiulcer actions and are highly safe, thus the antiulcer drugs containing the compounds are useful as a preventive and curative medicine against acute and chronic gastric ulcers, duodenal ulcers and gastric hyperacidities.

DESCRIPTION Technical Field

This invention relates to novel substituted acetamide derivatives, theircyclodextrin inclusion compounds, a process for their preparation andantiulcer drugs containing the same.

Background Art

The developmental mechanism of a peptic ulcer is complicated because itis influenced by a variety of factors. Peptic ulcers are considered tobe caused when the balance between aggressive factors (inhibition ofgastric acid secretion) and protective factors (cytoprotective action)for the tunica mucosa of the stomach is lost. It is therefore effectivepreventive or curative means to inhibit the secretion of the gastricacid serving as an aggressive factor.

Hitherto, in the clinical field, anticholinergic agents and histamine H₂receptor blockers such as cimetidine have widely been used as effectiveagents for suppressing the gastric acid secretion.

However, the anticholinergic agents are accompanied by side-effects suchas the suppression of the discharge movement of the stomach, thirst,mydriasis and inhibition of perspiration. What is worse, they cannoteffectively prevent the aggravation of the ulcer nor prevent the relapseof it even when they are used in such amounts that would substantiallyinhibit the gastic acid secretion. Meanwhile, cimetidine causesundesirable side effects such as central actions and an antiandrogeneffect. Furthermore, a problem arises in that the protective factors inthe tunica mucosa function less if cimetidine is administered for a longterm. As a result, it causes the relapse of the ulcer when theadministration of cimetidine has been stopped.

Therefore, a desire has been arisen for an improved antiulcer drugcapable of effectively controlling the secretion of gastric acid whichserves as an aggressive factor, and having a protective factorpotentiation action (cytoprotective action).

The inventors have studied for the purpose of finding an improvedantiulcer compound capable of effectively controlling the secretion ofgastric acid which serves as an aggressive factor, and having aprotective factor potentiation action (cytoprotective action). As aresult, the present invention was achieved, in which a substitutedacetamide derivative of formula (I), its salts, and inclusion compoundsthereof in cyclodextrin were found to meet the above objects.

DISCLOSURE OF INVENTION

According to the present invention, there is provided substitutedacetamide derivatives, salts thereof, inclusion compounds obtained bycausing said substituted acetamide derivatives or the salts thereofincluded in cyclodextrin and antiulcer drugs comprising them as activeingredient, the substituted acetamide derivative being represented bythe following general formula (I): ##STR3## [in which Y represents apiperidino group, 1-pyrrolidinyl group, or 3-hydroxy-1-pyrrolidinylgroup, and Z represents a group selected from the group consisting of(a) to (e):

(a) a cyano group;

(b) a group expressed by ##STR4## (in which l represents an integer from0 to 2, n represents an integer from 1 to 3, R¹ represents a hydroxygroup, 1,2-dihydroxyethyl group, 1-hydroxyethyl group,2-phenyl-1-hydroxyethyl group, 2-hydroxyethoxy group, loweralkoxycarbonyl group, 2,2-dimethyl-1,3-dioxolan-4-yl group, or a loweracyloxymethyl group);

(c) a group expressed by ##STR5## (in which R² represents an aminogroup, lower alkylamino group, di(2-hydroxyethyl)amino group, loweralkyl group, or a lower alkoxy group);

(d) a group expressed by ##STR6## (in which R³ and R⁴ respectivelyrepresent a hydrogen atom, or a lower alkyl group);

(e) a group expressed by ##STR7## (in which l represents an integer from0 to 2, and R⁵ and R⁶ respectively represent a hydrogen atom or a loweralkyl group).

BEST MODE OF THE INVENTION

The lower alkyl group of compound (I) according to the present inventionis exemplified by a straight or a branched chain alkyl group having 1 to6 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl and tert-butyl groups. The lower alkozy group is exemplified bya straight or a branched chain alkoxy group having 1 to 6 carbon atoms,preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxyand tert-butoxy groups. The lower acyl group is exemplified by astraight or branched chain alkanoil group having 2 to 7 carbon atoms,preferably acetyl, propionyl, n-butyryl and isobutyryl groups. Thehalogen atom is exemplified by fluorine atoms, bromine atoms, chlorineatom and iodine atom, among which bromine atom and chlorine atom arepreferred.

The salts of compound (I) according to the present invention are thosewhich are medicinally accepted, which include salts of organic acidssuch as acetic acid, maleic acid, citric acid, oxalic acid, fumaric acidand hybenzoic acid; salts of inorganic acid such as hydrochloric acid,sulfuric acid and nitric acid and bromic acid.

Compounds (I) according to the present invention can be prepared, forexample, by any of the following preparation methods A to E.

<PREPARATION METHOD A> ##STR8## [in which X represents a halogen atom, Arepresents a hydrogen atom, potassium atom or a sodium atom, Zarepresents (a) a cyano group or (b') a group expressed by --S--(CH₂)_(n)--R¹ (in which n and R¹ respectively represent the same meanings asdescribed before].

That is, the compounds of general formula (Ia) according to the presentinvention can be prepared by reacting an acetamide derivative of generalformula (II) and a compound of general formula (III).

It is preferable that the reaction according to preparing method A beperformed in a solvent which does not influence the reaction. Thesolvent is exemplified by: alcohol such as methanol, ethanol andpropanol; amides such as dimethylformaldehyde and diethylformaldehyde;ethers such as tetrahydrofuran and dioxane; hydrocarbon halides such asdichloromethane and chloroform; aromatic hydrocarbons such as benzene,toluene and xylene; acetonitryl; and dimethyl sulfoxide. Reactiontemperature and reaction time may be changed according to the startingmaterials, and generally, 0° to the reflux temperature under atmosphericpressure.

<PREPARATION METHOD B> ##STR9## [in which, B represents a loweralkoxycarbonylmethyl group and Zb represents a group selected from (a)to (e):

(a) a cyano group;

(b) a group expressed by ##STR10## (in which l represents an integerfrom 0 to 2, n represents an integer from 1 to 3 and R^(1a) represents ahydroxy group, 1,2-dihydroxyethyl group, 1-hydroxyethyl group,2-phenoxy-1-hydroxyethyl group, 2-hydroxyethoxy group or2,2-dimethyl-1,3-dioxolan-4-yl group),

(c) a group expressed by ##STR11## (in which R^(2a) represents an aminogroup, a lower alkyl amino group, di(2-hydroxyethyl)amino group or alower alkoxy group),

(d) a group expressed by ##STR12## (in which R³ and R⁴ respectivelyrepresent a hydrogen atom or a lower alkyl group),

(e) a group expressed by ##STR13## (in which l, R⁵ and R⁶ respectivelyrepresent a hydrogen atom or a lower alkyl group).

That is, a compound according to the present invention of generalformula (Ib) can be prepared by reacting an amine derivative of generalformula (IV) and a compound of general formula (V).

It is preferable that the reaction in preparation method B be performedin a solvent which does not influence the reaction. The solvent isexemplified by: alcohol such as methanol, ethanol and propanol; amidessuch as dimethylformamide and diethylformamide; ethers such astetrahydrofuran and dioxane; acetonytryl; dimethylsulfoxide; hydrocarbonhalides such as dichloromethane and chloroform; and aromatichydrocarbons such as benzene, toluene and xylene. Reaction temperatureand reaction time may be changed according to the starting materials,and generally, 0° to the reflux temperature under atmospheric pressure.

PREPARATION METHOD C ##STR14## [in which n and Y respectively representthe same meanings as described before].

That is, the compound of general formula (Ic) according to the presentinvention can be prepared by reacting an amine derivative of generalformula (IV) and a compound of general formula (VI).

The reaction according to preparation method C is performed by using anon-proton solvent which does not influence the reaction, the solventbeing exemplified by: aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as tetrahydrofuran and dioxane; and amides such asdimethylformamide and diethylformamide. Reaction temperature andreaction time may be changed according to the starting materials, andgenerally, 0° C. to the reflux temperature under atmospheric pressure.

PREPARATION METHOD D ##STR15## [in which R^(2b) represents a loweralkoxy group, R^(2c) represents an amino group, a lower alkylamino groupand di(2-hydroxyethyl)amino group, and Y represents the same meaning asdescribed before].

That is, a compound of general formula (Id) according to the presentinvention can be prepared by reacting a compound of general formula (Ie)and a compound of general formula (VII).

The reaction according to the preparation method D is performed by usinga solvent which does not influence the reaction, the solvent beingexemplified by: alcohol such as methanol, ethanol and propanol; aromatichydrocarbons such as benzene, toluene and xylene; amides such asdimethylformamide and diethylformamide; ethers such as tetrahydrofuranand dioxane; hydrocarbon halides such as dichloromethane and chloroform.Reaction temperature and reaction time may be changed according to thestarting materials, and generally, 0° to the reflux temperature underatmospheric pressure.

PREPARATION METHOD E ##STR16## [in which Zc represents a group expressedby: ##STR17## (in which n, R¹, R⁵ and R⁶ respectively represent the samemeaning as described before), and Zd represents a group expressed by:##STR18## (in which q represents an integer 1 or 2; n, R¹, R⁵ and R⁶respectively represent the same meanings as described before), and Yrepresents the same meaning as described before].

That is, a compound of general formula (If) according to the presentinvention can be prepared by oxidizing a compound of general formula(Ig).

In preparation method E, a conventional oxidation reaction for thioethercompounds may be applied, wherein an oxidizing agent is reacted in asuitable solvent. The solvent is exemplified by: alcohol such asethanol; aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as tetrahydrofuran and dioxane; hydrocarbon halides such aschloroform and methylen chloride. The oxidizing agent is exemplified byorganic peroxides such as periodic acid, hydrogen peroxide,methachloroperbenzoic acid, perphhalic acid and permaleic acid. Forexample, the oxidation to sulfinyl of q=1 may be performed by reactingperiodic acid in hydrated alcohol, while the oxidation to sulfinyl ofq=2 may be performed by reacting hydrogen peroxide in organic acid.

The inclusion compounds of compound (I) according to the presentinvention can be prepared by a usual method by using cyclodextrin suchas α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. In the case wherethe compound according to the present invention is a water insolublecompound and/or an amorphous compound, it can be converted into a watersoluble compound and/or a crystallizable compound by forming inclusioncompounds of cyclodextrin, which is advantageous for the manufacture ofmedicines.

The toxicity and anti-ulcer activity of compounds (I) according to thepresent invention will be described hereinbelow.

The aggressive factor inhibition action was evaluated from the effectson the gastric acid secretion of anesthesia fistula rats by histamine,while the protective factor potentiation action was evaluated from theeffects observed in a hydrochloric acid-ethanol ulcer model. In theTables, the column of test compounds indicates Example numbers where thecompounds are prepared.

(1) Effects on Gastric Acid Secretion of Anesthesia Fistula Rat byHistamine:

Male SD rats (Japan Charles River Co., Ltd.) each weighing 180 to 200 gwere fasted for 24 hours before celiotomy with etherrization. A feedingtube (fr. 3.5) for injecting test medicines was inserted into theduodenum, and the pylorus was ligatured. A polyethylene tube (innerdiameter: 7 mm) was used in the anterior stomach and gastric fistula wasperformed. After washing the inside of the stomach with heatedphysiological salt solution (37° C.) several times, the body was closed.A tube with a fin was inserted into the caudal vein and was fastenedwith a tape and it was connected to a infusion pump (Harvard). The ratswere enclosed in a KN Ballman II cage (Natsume Seisakusho). Gastricjuice flowed from the fistula was collected with a messcylinder everyone hour. Starting form one hour after the operation, histamine wascontinuously injected at a rate of 1.4 ml/hour through the caudal vein.Then, test compounds suspended in 0.5% sodium caboxy methyl cellulose(Na-CMC) were administered one hour after the start of the histamineinjection. The gastric juice thus extracted in a period from one hourafter the administration of the chemical to four hours after that wastitrated by using an automatic titration aparatus (Kyoto Electronic)with 0.1N NaOH to adjust pH 7, and the quantity of the gastric juice wasmeasured to obtain the total acid output.

The inhibition rate (%) of the gastric acid secretion was calculatedform the following equation, which results are shown in Table 1.##EQU1##

                  TABLE 1                                                         ______________________________________                                        Effects on Gastric Acid Secretion of Anesthesia                               Fistula Rat by Histamine                                                                 Dose   Gastric acid secretion                                                 (mg/kg)                                                                              inhibition effect (%)                                       ______________________________________                                        Test                                                                          Compounds                                                                     Example   2      30       79.5                                                          7      30       59.4                                                          8      30       70.9                                                         12      30       55.4                                                Comparative                                                                   Compounds                                                                     Cimetidine   30       32.3                                                    Roxatidine   30       68.8                                                    ______________________________________                                    

As shown in Table 1, the compounds according to the present inventioneffectively inhibited the gastric acid secretion of anesthesia fistularat, which was caused by the histamine stimulus.

(2) Hydrochloric Acid-Ethanol Ulcer Test

Male SD rats each weighing 170 to 190 g were fasted for 24 hours, and 1ml of 150 mM hydrochloric acid-60% ethanol was orally administered toeach rat. After one hour, rats were clubbed to death, and the stomachwas extracted. 10 ml of 2% formalin solution was applied to the stomachfor fixing for 10 minutes. The length (mm) of the injuries in the tunicamucosa taken place in the glandular stomach was measured under astereoscopic microscope. The total length of the injuries of theindividual was taken as the ulcer index.

Test compounds or control (1% Na-CMC) were orally administered in anamount of 0.5 ml/100 g, 30 minutes before the administration ofhydrochloric acid-ethanol.

The ulcer inhibition rate was calculated by the following equation,which results are shown in Table 2. ##EQU2##

                  TABLE 2                                                         ______________________________________                                        Effects on Ulcer Formation Caused by Hydrochloric                             Acid-Ethanol                                                                            Dose                                                                          (mg/kg)                                                                              Ulcer Inhibition Rate(%)                                     ______________________________________                                        Test                                                                          Compounds                                                                     Example 2   100      72.5                                                     Comparative                                                                   Compounds                                                                     Cimetidine  100      22.7                                                     Roxatidine  100      69.4                                                     ______________________________________                                    

As shown in Table 2, the compounds according to the present inventioneffectively inhibit the ulcer formation on an ulcer model caused byhydrochloric acid-ethanol, thus have a preventive factor potentiationaction.

(3) Toxicity test

The compounds according to Examples 2, 7, 8 and 12 were respectivelysuspended in 3% gum arabic solution and continuously, forcedly andorally administrated to three ICR:Crj 5 week old male mice for 14 daysat a dose of 500 mg/kg/day. No rat died and weight loss was notobserved. In an acute toxicity test by an oral administration of thecompounds, the LD₅₀ value of the compound according to Example 2 was2383 mg/kg, and the LD₅₀ value caused form Roxatidine was 755 mg/kg.

As described above, it has been confirmed that the compounds accordingto the present invention are excellent antiulcer agents having both theaggressive factor inhibition action and the protective factorpotentiation action (cytoprotective effect). The toxicity test revealedthat the compounds according to the present invention are very safecompounds. Thus, the antiulcer drugs containing the compounds accordingto the present invention are useful as preventive and curative medicinesagainst acute and chronic gastric ulcer, duodenal ulcer, gastrichyperacidity.

The compounds (I) and their salts according to the present invention canbe administered to a mammal including human as a preventive and curativemedicine against acute and chronic gastric ulcers, duodenal ulcers,gastric hyperacidities. In general, it may be orally or non-orallyadministered in various forms of a medical composition which can bemedicinally permitted.

For the oral administration, the compounds may be formed into tablets,powders and capsules together with suitable additives includingexcepients such as lactose, mannitols, corn starch and crystallinecellulose; binders such as a cellulose derivative, gum arabic andgelatine; disintegrators such as carboxymethyl cellulose calcium; andlubricants such as talc and magnesium stearate.

For the non-oral administration, they can be formed into injection drugsin combination with, for example, water, ethanol or glycerol.

The dosage may be determined depending upon age, symptom, effectsobtained, manner of administration, and administration period. It ispreferable that the dosage be once to three times a day from 1 to 500mg/kg/day in the case of the oral administration.

EXAMPLES

The present invention will be described in details by way of examples.The present invention, however, is not limited to these examples.

EXAMPLE 1

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-cyanoacetamide ##STR19##

1.59 g of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-chloroacetamidewas dissolved in 9 ml of dimethylformamide in accordance withpreparation method A, and 637 mg of potassium cyanide was added thereto,followed by stirring at external temperature of 90° C. for 1.5 hours.After the reaction solution was cooled down, saturated NaCl solution wasadded and extraction was carried out with ethyl acetate and dried overmagnesium sulfate. Ethyl acetate was distilled off under reducedpressure. The thus obtained residue was dissolved in benzene, and thenhydrochloric acid-ether solution was added thereto to obtain a depositedoily substance by an inclination method. Then, aqueous saturated sodiumhydrogencarbonate solution was added to the thus obtained oily substanceand extracted again by ethyl, dried over magnesium sulfate, distilledunder reduced pressure to obtain a brown oily substance. This wassubjected to silica gel column chromatography (solvent;chloroform:methanol=7:1). 418 mg of light brown oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-cyanoacetamide was obtained.

NMR spectrum δ(CDCl₃): 1.3 to 1.80 (6H, m) 1.80 to 2.25 (2H, m), 2.25 to2.70 (4H,m), 3.40 (2H, s), 3.50 (2H, s), 3.20 to 3.70 (2H, m), 4.05 (2H,m), 6.60 to 7.40 (5H, m)

IR spectrum (liquid film, cm⁻¹): 2240, 1650

To the thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-cyanoacetamide was addedsaturated maleic acid-ether solution to produce a maleic acid salt.

EXAMPLE 2

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamid##STR20##

The title compound was prepared in accordance with preparation method A.639 mg of 85% pottassium hydroxide was dissolved in 30 ml methanol, and2.39 mg of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-chloroacetamideand 600 mg of 2-mercaptoethanol were dropped thereto and stirred at roomtemperature for one hour. Then, methanol was condensed under reducedpressure. Water was added to the thus obtained residue and extractedwith chloroform. The extracted solution was dried over magnesium sulfateand chloroform was distilled off under reduced pressure. Light brownoily substance was obtained.

The oily substance was then subjected to silica gel columnchromatography (solvent; chloroform:methanol=4:1). As a result, 2.20 gof oily N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamide was obtained.

NMR spectrum δ(CDCl₃): 1.25 to 1.75 (6H, m), 1.85 to 2.55 (6H, m), 2.75(2H, t), 3.27 (2H, s), 3.45 (2H, s), 3.10 to 3.95 (5H, m), 4.09 (2H, t),6.65 to 7.60 (5H, m)

IR spectrum (liquid film, cm⁻¹): 3300, 1650

The thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamidewas converted to a hydrochloric acid salt by a hydrochloric acid-ethanolsolution.

EXAMPLE 3

16.7 g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamideobtained in Example 2 was dissolved in 50 ml ethanol and added with asolution obtained by dissolving 11 g of 2-(4-hydroxybenzoyl)-benzoicacid (hybenzoic acid) in 70 ml ethanol, and stirred. The reactionsolution was substantially halved by condensation and then allowed tostand at 5° C. for 24 hours. Crystals precipitated were collected byfiltration and 25 g (90%) ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamidehybenzoic acid salt was obtained.

Melting point: 145° to 148° C.

NMR δ(DMSO): 1.33 to 1.53 (6H, br), 1.84 (2H, m), 2.42 to 2.56 (4H, br),2.63 (2H, m), 3.11 (2H, s), 3.21 (2H, q), 3.54 (2H, t), 3.58 (2H, s),3.95 (2H, t), 6.78 to 7.96 (12H, m), 8.09 (1H, br)

IR (KBr) cm⁻¹ : 3350, 2950, 1640, 1580, 1390, 1290, 1150, 930, 845, 760

EXAMPLE 4

14.4 g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamideprepared in Example 2 was dissolved in 50 ml benzene, and 200 ml ethersolution containing 4.55 g maleic acid was added thereto. Thesupernatant was removed by inclination, and the residue was washed with200 ml ether followed by drying-up under reduced pressure. 13.8 g ofoily maleic acid salt was obtained.

NMR δ(CDCl₃): 1.24 (1H, br), 1.85 to 1.98 (5H, m), 2.05 (2H, m), 2.54 to2.68 (2H, br), 3.76 (2H, t), 3.29 (2H, s), 3.48 (2H, q), 3.46 to 3.60(2H, m), 3.79 (2H, t), 4.02 (2H, t), 4.11 (2H, s), 6.34 (2H, s), 6.84 to7.32 (4H, m), 7.50 (1H, s)

IR (liquid film, cm⁻¹): 3300, 1640, 1580, 1340, 1260, 860

EXAMPLE 5

15 g of γ-cyclodextrin was dissolved in 60 ml water. 2.1 g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamideobtained in Example 2 was added thereto and subjected to ultrasonictreatment for 15 minutes. Then, it was stirred at room temperature for20 hours. Crystals were collected by filtration, washed twice with 10 mlwater, recrystalized from water, dried up at 60° C. for 6 hours toobtain 13.6 g of γ-cyclodextrin inclusion compound ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamide.

Melting point: about 275° C. (dec.)

IR: 1640 cm⁻¹

EXAMPLE 6

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-sulfinyl)acetamide##STR21##

The title compound was prepared according to preparation method E. 1.23g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamideprepared in Example 2 and 738 mg of aqueous hydrogen peroxide solutionwere added to 3 ml acetic acid. The solution was stirred at roomtemperature for 1.5 hours and was made alkaline with saturated aqueoussodium bicarbonate solution, which was extracted with chloroform. Theextracted solution was dried over potassium carbonate, and thenchloroform was distilled off under reduced pressure. Oily substance wasobtained. The obtained substance was then subjected to silica gel columnchromatography (solvent; chloroform:methanol=3:1). As a result, 512 mgof oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-sulfinyl)acetamidewas obtained.

NMR spectrum δ(CDCl₃): 1.32 to 1.84 (6H, m), 1.88 to 2.18 (2H, m), 2.31to 2.71 (4H, m), 2.88 to 4.28 (12H, m), 6.66 to 7.42 (4H, m), 7.53 to7.96 (1H, br)

IR spectrum (liquid film, cm⁻¹): 1655, 1260, 1035

EXAMPLE 7

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethylsulfonyl)acetamide##STR22##

The title compound was prepared according to preparation method E. 1.30g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamideprepared in Example 2 was dissolved in 8 ml acetic acid, to which 8.34 gof aqueous 30% hydrogen peroxide solution was added. It was then stirredat external temperature of 70° C. for 1.5 hours. 10 ml water was addedto the reaction solution and condensed under reduced pressure. Theobtained residue liquid was neutralized with saturated aqueous sodiumhydrogencarbonate solution and then NaCl was added to make an aqueoussaturated solution, which was extrated with chloroform. The chloroformlayer was dried over magnesium sulfate, and chloroform was distilled offunder reduced pressure. Oily substance was obtained. The thus obtainedoily substance was then subjected to silica gel column chromatography(solvent; chloroform:methanol=4:1). As a result, 572 mg of light yellowoilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-sulfonyl)acetamidecontaining a slight quantity of acetic acid was obtained.

NMR spectrum δ(CDCl₃): 1.35 to 2.30 (8H, m), 2.35 to 2.95 (4H, m), 3.10to 4.45 (13H, m), 6.60 to 7.50 (4H, m), 7.70 to 8.25 (1H, m)

IR spectrum (liquid film, cm⁻¹): 3300, 1315, 1120

The thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethylsulfonyl)acetamidewas convered to a hydrochloric acid salt with hydrochloric acid-ethanolsolution.

EXAMPLE 8

N-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamide##STR23## Preparation method A was followed. 361 mg of 85% potassiumhydroxide was dissolved in 35 ml methanol, to which 1.13 g ofN-[3-[3-(1-(pyrrolidinylmethyl)phenoxy]propyl]-2-chloroacetamide and 324mg of 2-mercaptoethanol were added and stirred at room temperature for 2hours. Methanol was then condensed under reduced pressure. Then, 30 mlwater was added to the thus obtained residue, and the extracted solutionextracted with chloroform was dried over magnesium sulfate. Chloroformwas distilled off under reduced pressure. Light brown oily substance wasobtained.

This substance was subjected to silica gel column chromatography(solvent; chloroform:methanol=4:1). 836 mg of oilyN-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamidewas obtained.

NMR spectrum δ(CDCl₃): 1.70 to 2.35 (6H, m) 2.35 to 2.90 (6H, m), 3.15to 4.36 (11H, m), 6.65 to 7.63 (5H, m)

IR spectrum (liquid film, cm⁻¹): 3300, 1650

EXAMPLE 9

N-[3-[3-(1-(pyrrolidinylmethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-sulfinyl)acetamide##STR24## Preparation method E was followed. 918 mg ofN-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamideobtained in Example 8 was dissolved in 3 ml acetic acid, to which 549 mgof aqueous 31% hydrogen peroxide solution was dropped at roomtemperature. Stirring was continued at the same temperature. After 1.5hours, it was then added into saturated aqueous sodium hydrogencarbonatesolution, made saturated by sodium chloride and extracted by n-butanol.The extracted solution was dried over magnesium sulfate and n-butanolwas distilled off under reduced pressure. 804 mg of light brown oilysubstance was obtained. The thus obtained substance was then subjectedto alumina column chromatography (Melck Co., Art 1067, solvent;chloroform:methanol=7:1).

671 mg of oilyN-[3-[3-(1-(pyrrolidinylmethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-sulfinyl)acetamidewas obtained.

NMR spectrum δ(CDCl₃): 1.60 to 2.20 (6H, m), 2.30 to 2.75 (4H, m), 3.03(2H, t), 3.20 to 4.25 (11H, m), 6.65 to 7.65 (5H, m)

IR spectrum (liquid film, cm⁻¹): 3275, 1650, 1025

EXAMPLE 10

N-[3-[3-(1-(pyrrolidinylmethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-sulfonyl)acetamide##STR25## Preparation method E was followed. 1.27 g ofN-[3-[3-(1-(pyrrolidinylmethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamideobtained in Example 8 was dissolved in 8 ml acetic acid, to which 9.11 gof aqueous 31% hydrogen peroxide solution was added and stirred atexternal temperature of 65° C. 1.5 hours after, 10 ml water was addedand condensed under reduced pressure. The residual solution was addedwith 16 ml of saturated aqueous sodium hydrogencarbonate solution andextracted with chloroform. The extracted solution was dried overmagnesium sulfate, and then chloroform was distilled off under reducedpressure to obtain a brown oily substance. This was then subjected tosiliga gel column chromatography (solvent; chloroform:methanol=4:1). Asa result, 377 mg of colorless oilyN-[3-[3-(1-pyrrolidinylmethyl)phenoxyl]propyl]-2-(2-hydroxyethyl-1-sulfonyl)acetamidecontaining a slight quantity of acetic acid was obtained.

NMR spectrum δ(CDCl₃): 1.75 to 2.30 (6H, m), 2.65 to 3.25 (4H, m), 3.25to 3.70 (m), 3.80 to 4.50 (m), 6.65 to 7.75 (5H, m)

IR spectrum (liquid film; cm⁻¹): 3300, 1650, 1310, 1115

EXAMPLE 11

N-[3-[3-(1-piperidinomethyl)phenoxy]propyl]-2-(2-acetoxyethylsulfonyl)acetamide##STR26##

897 mg ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethylsulfonyl)acetamideobtained in Example 7 was dissolved in 428 mg of acetic anhydride and462 mg of pyridine and stirred at external temperature of 55° C. for 2hours. Then, it was added to a mixture of 20 ml saturated aqueous NaClsolution and 15 ml saturated aqueous sodium hydrogencarbonate solutionand was extracted with chloroform. The extracted solution was dried overmagnesium sulfate, and then chloroform was distilled off under reducedpressure to obtain an oily substance. The thus obtained substance wassubjected to silica gel column chromatography (solvent;chloroform:methanol=4:1). As a result, 583 mg of light brown oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-acetoxyethylsulfonyl)acetamidecontaining a slight quantity of acetic acid was obtained.

NMR spectrum δ(CDCl₃): 1.40 to 2.20 (5H, m), 2.10 (3H, s), 2.60 to 3.05(4H, m), 3.05 to 4.70 (12H, m), 6.60 to 7.70 (4H, m), 8.05 to 8.40 (1H,m)

IR spectrum (liquid film, cm⁻¹): 1740, 1665, 1320, 1120

The thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-acetoxyethylsulfonyl)acetamidewas converted to a maleic acid salt by a saturated ether solution ofmaleic acid.

NMR spectrum δ(CDCl₃): 1.60 to 2.30 (6H, m), 2.05 (3H, s), 2.30 to 3.05(6H, m), 3.20 to 3.85 (6H, m), 3.95 to 4.50 (4H, m), 6.35 (2H, s), 6.70to 7.60 (5H, m).

IR spectrum (liquid film, cm⁻¹): 1735, 1640

EXAMPLE 12

N-[3-[3-(1-pirrolidinylmethyl)phenoxy]propyl]-2-(2-acetoxyethyl-1-thio)acetamide##STR27##

404 mg ofN-[3-[3-(1-pyrrolidinyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamideobtained in Example 8 was dissolved in a mixture of 261 mg aceticanhydride and 250 mg pyridine and stirred at external temperature of 55°C. for 30 minutes. Then, 20 ml of saturated aqueous NaCl solution and 15ml saturated aqueous sodium hydrogencarbonate solution were addedthereto and extracted with chloroform. The extracted solution was driedover magnesium sulfate, and then chloroform was distilled off underreduced pressure. The obtained residue was subjected to silica gelcolumn chromatography (solvent; chloroform:methanol=4:1). As a result,318 mg of oilyN-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]-2-(2-acetoxyethyl-1-thio)acetamidewas obtained.

NMR spectrum δ(CDCl₃): 1.60 to 2.30 (6H, m), 2.05 (3H, s), 2.30 to 3.10(6H, m), 3.10 to to 3.85 (6H, m) 3.95 to 4.40 (4H, m), 6.70 to 7.60 (5H,m)

IR spectrum (liquid film, cm⁻¹): 1735, 1645

The thus obtainedN-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]-2-(2-acetoxyethyl-1-thio)acetamidewas converted into a maleic acid salt with a saturated ether solution ofmaleic acid.

EXAMPLE 13

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-acetoxyethyl-1-thio)acetamide##STR28##

1.03 g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamideobtained in Example 2 was dissolved in a mixture of 1.19 g of aceticanhydride and 981 mg of pyridine and stirred at external temperature of60° C. for 2 hours. Then, 10 ml water and 10 ml saturated aqueous sodiumhydrogencarbonate solution were added and extracted with chloroform. Theextracted solution was dried over magnesium sulfate, and then chloroformwas distilled off under reduced pressure. The obtained residue wassubjected to silica gel column chromatography (solvent;chloroform:methanol=4:1). As a result, 637 mg of oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-acetoxyethyl-1-thio)acetamidewas obtained.

NMR spectrum δ(CDCl₃): 1.25 to 1.78 (6H, m), 1.78 to 2.56 (6H, m), 2.01(3H, s), 2.78 (2H, t), 3.22 (2H, s), 3.20 to 3.72 (4H, m), 3.78 to 4.42(4H, m), 6.51 to 7.61 (5H, m)

IR spectrum (liquid film, cm⁻¹): 1745, 1650

EXAMPLE 14

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2,3-dihydroxypropyl-1-thio)acetamide##STR29## Preparation method A was followed. 375 mg of 85% potassiumhydroxide was dissolved in 20 ml methanol, to which were added at once 5ml methanol solution of 399 mg 3-mercapto-1,2-propanediol and 5 mlmethanol solution of 1.20 gN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-chloroacetamide. Thereaction solution was stirred at room temperature for one hour, andmethanol was condensed under reduced pressure. 60 ml saturated aqueousNaCl solution was added to the obtained residue and extracted withchloroform. The extracted solution was dried over magnesium sulfate, andthen chloroform was distilled off under reduced pressure to obtain alight brown oily substance. The thus obtained substance was subjected tosilica gel column chromatography (solvent; chloroform: methanol=4:1). Asa result, 828 mg of colorless oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2,3-dihydroxypropyl-1-thio)acetamidewas obtained.

NMR spectrum δ(CDCl₃): 1.39 to 1.80 (6H, m), 1.80 to 2.22 (2H, m), 2.30to 2.70 (4H, m), 2.74 (2H, d), 3.26 (2H, s), 3.50 (2H, s), 3.32 to 3.82(7H, m), 4.10 (2H, t), 6.65 to 7.80 (5H, m)

IR spectrum (liquid film, cm⁻¹): 3350, 1630

The thus obtained N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2,3-dihydroxypropyl-1-thio)acetamide was convertedinto a hydrochloric acid salt with hydrochloric acid-ethanol solution.

EXAMPLE 15

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methylthio]acetamide##STR30##

50 ml acetone and 5 ml of 7% hydrochloric acid-ethanol solution wereadded to 2.10 g of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2,3-dihydroxypropyl-1-thio)acetamide prepared inExample 14 and refluxed over 2 hours. Then, the solvent was distilledoff under reduced the pressure. 10 ml saturated aqueous NaCl solutionand 10 ml saturated aqueous sodium hydrocarbonate solution were added tothe residue and extracted with ethyl acetate. The extracted solution wasdried over magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The obtained light brown oily substance wassubjected to silica gel column chromatography (solvent;chloroform:methanol=5:1). 594 mg of oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methylthio]acetamidewas obtained.

NMR spectrum δ(CDCl₃): 1.33 (3H, s), 1.41 (3H, s), 1.30 to 1.80 (6H, m),1.80 to 2.25 (2H, m), 2.25 to 2.60 (4H, m), 2.71 (2H, d), 3.30 (2H, s),3.45 (2H, s), 3.40 to 3.85 (2H, m), 3.85 to 4.45 (5H, m), 6.60 to 7.50(5H, m)

IR spectrum (liquid film, cm⁻¹): 1645

EXAMPLE 16

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(ethoxycarbonylmethylthio)acetamide##STR31## Preparation method A was followed. 778 mg of 85% potassiumhydroxide was dissolved in 50 ml ethanol. Then, 10 ml ethanol solutionof 3.00 g of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-chloroacetamideand 1.14 g of 2-mercapto ethyl acetate were added to this solution. Itwas stirred at room temperature for 30 minutes, and ethanol wascondensed under reduced pressure. Then, water was added to the obtainedresidue and extracted with chloroform. The extracted solution was driedover magnesium sulfate, and chloroform was distilled off under reducedpressure. Light brown oily substance was obtained. The thus obtainedsubstance was subjected to silica gel column chromatography (solvent;ethyl acetate). As a result, 2.22 g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(ethoxycarbonylmethylthio)acetamidewas obtained.

NMR spectrum δ(CDCl₃): 1.25 (3H, t), 1.30 to 1.75 (6H, m), 1.85 to 2.20(2H, m), 2.20 to 2.60 (4H, m), 3.27 (2H, s), 3.35 (2H, s), 3.44 (2H, s),3.57 (2H, t), 4.06 (2H, t), 4.11 (2H, t), 6.70 to 7.50 (5H, m)

IR spectrum (liquid film, cm⁻¹): 1730, 1650

Melting point: 137° to 137.5° C.

EXAMPLE 17

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(ethoxycarbonylmethylsulfonyl)acetamide##STR32## Preparation method E was followed. 2.13 g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(ethoxycarbonylmethylthio)acetamideobtained in Example 16 was dissolved in 20 ml acetic acid, to which 20ml of aqueous 30% hydrogen peroxide solution was added and stirred atexternal temperature of 70° C. for 2 hours. Then, water was added to thereaction solution and condensed under reduced pressure. The obtainedresidual liquid was neutralized with saturated sodium hydrogencarbonateand was added with NaCl to make a saturated aqueous solution, followedby extraction with chloroform. The extracted solution was dried overmagnesium sulfate, and then chloroform was distilled off under reducedpressure. The obtained residue was subjected to silica gel columnchromatography (solvent; chloroform:methanol=4:1). 1.34 g of oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(ethoxycarbonylmethylsulfonyl)acetamidecontaining a slight quantity of acetic acid was obtained.

NMR spectrum δ(CDCl₃): 1.30 (3H, t), 1.40 to 2.25 (8H, m), 2.35 to 2.80(4H, m), 3.17 (2H, s), 3.56 (2H, t), 4.35 (4H, brs), 3.95 to 4.55 (4H,m), 6.70 to 7.70 (5H, m)

IR spectrum (liquid film, cm⁻¹): 1740, 1675, 1335, 1120

The thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(ethoxycarbonylmethylsulfonyl)acetamidewas converted into a hydrochloric acid salt with hydrochloricacid-ethanol solution.

EXAMPLE 18

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-carbamoylacetamide ##STR33##Preparation method D was followed. 1.37 g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-methoxycarbonylacetamideprepared in Example 22 to be described later was dissolved in 30 ml of9.3% (w/v) ammonia-methanol solution and heated at 50° C. for 8 hours ina sealed tube. Then, methanol was distilled off under reduced pressure.The obtained residue was subjected to silica gel column chromatography(solvent; chloroform: methanol=4:1). 669 mg ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-carbamoylacetamide wasobtained as colorless crystals.

Melting point: 85.3° to 88.3° C.

NMR spectrum δ (CDCl₃): 1.35 to 1.80 (6H, m), 1.80 to 2.10 (2H, m), 2.20to 2.65 (4H, m), 3.20 (2H, s), 3.45 (2H, s), 3.55 (2H, t), 4.05 (2H, t),5.50 to 6.10 (2H, brs), 6.60 to 7.50 (5H, m)

IR spectrum (liquid film, cm⁻¹): 3300, 1650

The thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-carbamoylacetamide wasconverted into a hydrochloric acid salt with hydrochloric acid-ethanolsolution.

Melting point: 195.5° to 197.5° C.

EXAMPLE 19

N-[3-[3-(pyrrolidinylmetyl)phenoxy]propyl]-2-carbamoylacetamide##STR34## Preparation method D was followed. 1.30 g ofN-[3-[3-(1-pyrrolidinylmethl)phenoxy]propyl]-2-methoxycarbonylacetamideprepared in Example 23 to be described later was dissolved in 30 ml of9.3% ammonia-methanol solution and stirred at room temperature for 14hours in a sealed tube. Then, methanol was distilled off under reducedpressure. The obtained residue was subjected to silica gel columnchromatography (solvent; chloroform: methanol=6:1). 950 mg of oilyN-[3-[3-(pyrrolidinylmethl)phenoxy]propyl]-2-carbamoylacetamide wasobtained.

NMR spectrum δ(CDCl₃): 1.59 to 2.20 (6H, m), 2.37 to 2.79 (4H, m), 3.13to 3.79 (6H, m), 4.02 (2H, t), 6.26 to 7.92 (6H, m).

IR spectrum (liquid film, cm⁻¹): 2950, 1670, 1640

The thus obtainedN-[3-[3-(pyrrolidinylmethl)phenoxy]propyl]-2-carbamoylacetamide wasconverted into a hydrochloric acid salt with hydrochloric acid-ethanolsolution.

EXAMPLE 20

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-[N',N'-[di(2-hydroxyethyl)]carbomoyl]acetamide ##STR35## Preparation methodD was followed. 777 mg of diethanolamine was added to 1.58 g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-methoxycarbonylacetamideprepared in Example 22 to be described later and stirred at externaltemperature of 110° C. for 3 hours. The reaction solution was subjectedto silica gel column chromatography (solvent; chloroform: methanol=4:1).913 mg of light brown oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-[N',N'-[di(2-hydroxyethyl)]carbomoyl]acetamidewas obtained.

NMR spectrum δ (CDCl₃): 1.30 to 1.75 (6H, m), 1.80 to 2.15 (2H, m), 2.20to 2.65 (4H, m), 3.47 (2H, m), 3.35 to 4.80 (16H, m), 6.60 to 7.50 (4H,m), 7.82 (1H, brs)

IR spectrum (liquid film, cm⁻¹): 3300, 1645, 1625,

The thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-[N',N'-[di(2-hydroxyethyl)]carbomoyl]acetamidewas converted into a hydrochloric acid salt with hydrochloricacid-ethanol solution.

EXAMPLE 21

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-3-oxobutylamide ##STR36##Preparation method B was followed. 1.34 g of3-[3-(piperidinomethyl)phenoxy]propylamine was dissolved in 10 mlmethylene chloride, to which 527 mg of diketene was dropped.

Ten minutes after completion of the dropping, methylene chloride wasdistilled off under reduced pressure. The obtained residue was subjectedto silica gel column chromatography (solvent; chloroform:methanol=5:1).1.27 g of colorless oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-3-oxobutylamide was obtained.

NMR spectrum δ (CDCl₃): 1.30 to 1.80 (6H, m), 1.80 to 2.60 (6H, m), 2.25(3H, s), 3.25 to 3.75 (6H, m), 4.05 (2H, t), 6.60 to 7.55 (5H, m)

IR spectrum (liquid film, cm⁻¹): 1720, 1645

The thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-3-oxobutylamide was convertedto hydrochloric acid salt with hydrochloric acid - ethanol solution.

EXAMPLE 22

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-methoxycarbonylacetamide##STR37## Preparation method B was followed.

2.47 g of [3-[3-(piperidinomethyl)phenoxy]propylamine was dissolved n 40ml of dimethylmalonate and stirred at external temperature of 130° C.for 2 hours. Then, an excessive quantity of dimethylmalonate wasdistilled of under reduced pressure. Light brown oily substance wasobtained. The obtained substance was subjected to silica gel columnchromatography (solvent; chloroform:methanol=6:1). As a result, 3.06 gof oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-methoxycarbonylacetamide wasobtained.

NMR spectrum δ (CDCl₃): 1.30 to 2.15 (12H, m), 3.40 (2H, s), 3.51 (2H,s), 3.80 (3H, s), 3.20 to 4.30 (4H, s), 6.60 to 7.70 (5H, m)

IR spectrum (liquid film, cm⁻¹): 1735, 1645

The thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-methoxycarbonylacetamide wasconverted to a maleic acid salt with saturated ether solution of maleicacid.

EXAMPLE 23

N-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]-2-methoxycarbonylacetamide##STR38## Preparation method B was followed. 2.00 g of3-[3-(1-pyrrolidinylmethyl)phenoxy]propylamine was dissolved in 40 ml ofdimethylmalonate and stirred in an oil bath at 130° C. over 3 hours,followed by condensation under reduced pressure. The obtained residuewas subjected to silica gel column chromatography (solvent; ethylacetate). 2.50 g of oilyN-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]-2-methoxycarbonylacetamidewas obtained.

NMR spectrum δ (CDCl₃): 1.57 to 2.18 (6H, m), 2.36 to 2.78 (4H, m), 3.18to 3.79 (7H, m), 4.06 (2H, t), 3.66 to 7.75 (4H, m)

IR spectrum (liquid film, cm⁻¹): 2950, 1740, 1650

EXAMPLE 24

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-sulfamoylacetamide ##STR39##Preparation method B was followed. 1.36 g ofN-[3-[3-(piperidinomethyl)phenoxy]propylamine and 1.15 g of2-sulfamoylethylacetate were mixed and stirred at external temperatureof 130° C. over 4 hours. It is then subjected to silica gel columnchromatography (solvent; chloroform:methanol=4:1). 1.34 g of oilyN-[3-[3-(1-piperidinomethyl)phenoxy]propyl]-2-sulfamoylacetamide wasobtained.

IR spectrum (liquid film, cm⁻¹): 1655, 1440, 1155

EXAMPLE 25

N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2,5-dimethylimidazol-4-yl-methylthio)acetamide##STR40## Preparation method B was followed. 2.68 g of[3-[3-(piperidinomethyl)phenoxy]propylamine was added to 2.33 g of4-[(ethoxy carbonyl methyl)thio]methyl-2,5-dimethylimidazol and stirredin an oil bath of 110° C. for 6 hours. The obtained oily substance wassubjected to silica gel column chromatography (solvent; chloroform:methanol=7:1). 1.43 g ofN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2,5-dimethylimidazol-4-yl-methylthio)acetamidewas obtained.

NMR spectrum δ (CDCl₃): 1.37 to 1.73 (6H, m), 1.88 to 2.59 (12H, m),3.08 to 4.28 (10H, m), 6.63 to 7.43 (4H, m)

IR spectrum (liquid film, cm⁻¹): 2930, 1650, 1445, 1260

The thus obtainedN-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2,5-dimethylimidazol-4-yl-methylthio)acetamidewas converted to a hydrochloric acid salt with hydrochloric acid-ethanolsolution.

EXAMPLE 26

The compound of Example 2 was prepared in accordance with preparationmethod C.

2.50 g of [3-[3-(piperidinomethyl)phenoxy]phenoxy]propylamine dissolvedin 10 ml benzene was dropped into a solution of 20 ml benzene and 1.20 gof 1.4-thioxane-2-on under stirring at room temperature for one hour.Saturated ether solution of maleic acid was added to the reactionsolution until precipitation was completed. Then, it was cooled down,and the supernatant was removed. 50 ml of chloroform was added to theresidue and washed with saturated sodium carbonate solution.Furthermore, it was washed with 30 ml chloroform, and the chloroform wascombined again, followed by drying over sodium sulfate anhydride.Thereafter, chloroform was distilled off under reduced pressure. 3.41 gof oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl-2-(2-hydroxy-1-thio)acetamidewas obtained.

EXAMPLE 27

The compound of Example 2 was prepared in accordance with preparationmethod B.

2.03 g of 2-(2-hydroxyethyl-1-thio)ethylacetate was added to a 20 mlbenzene solution containing 2.84 g of[3-[3-(piperidinomethyl)phenoxy]propylamine under stirring at roomtemperature. Stirring was carried out for further 30 minutes. Then, itwas refluxed at 70° C. over one hour. After cooling down, a saturatedether solution of maleic acid was added to the reaction solution untilno precipitation was deposited. The supernatant was removed. The residuewas dissolved with 50 ml of chloroform, washed with saturated aqueoussodium hydrogencarbonate solution. Furthermore, the aqueous layer wasextracted with 30 ml of chloroform, and the chloroform was combinedagain and dried over sodium sulfate anhydride. Chloroform was distilledoff under reduced pressure. 2.50 g of oilyN-[3-[3-(piperidinomethyl)phenoxy]propyl-2-(2-hydroxyethyl-1-thio)acetamidewas obtained.

    ______________________________________                                        Medicine Preparation Example 1.                                               ______________________________________                                        Compound of Example 2  20 g                                                   Lactose               315 g                                                   Corn Starch           125 g                                                   Crystalline Cellulose  25 g                                                   ______________________________________                                    

The above ingredients were uniformly mixed, to which 200 ml of aqueous7.5% hydroxypropyl cellulose solution was added, followed by forming itinto granules by an extrusion granulating machine with a 0.5 mm-diameterscreen. The granules were immediately rounded by a rounding machine anddried.

    ______________________________________                                        Medicine Preparation Example 2                                                ______________________________________                                        Compound of Example 3 20 g                                                    Lactose               100 g                                                   Corn Starch           36 g                                                    Crystalline Cellulose 30 g                                                    Carboxymethylcellulose Calcium                                                                      10 g                                                    Magnesium stearate     4 g                                                    ______________________________________                                    

The above ingredients were uniformly mixed, and were formed into tabletseach weighing 200 mg on a single tablet-forming machine having a stampwhose diameter was 7.5 mm.

    ______________________________________                                        Medicine Preparation Example 3                                                ______________________________________                                        Compound of Example 7  40 g                                                   Lactose               232 g                                                   Corn Starch           108 g                                                   Polyvinyl Pyrrolidone  20 g                                                   ______________________________________                                    

The above ingredients were uniformly mixed, to which 180 ml of 70 (v/v)% isopropylalcohol was added. It was then formed into granules by anextrusion granulating machine with a 0.5 mm-diameter screen, and dried.The thus formed granules were encapsulated in #2 hard gelatinouscapsules, each contained 240 mg granules.

    ______________________________________                                        Medicine Preparation Example 4                                                ______________________________________                                        Compound of Example 8  3 g                                                    Polysolvate 80        20 g                                                    ______________________________________                                    

The above ingredients and 8 g of NaCl were dissolved in distilled waterto make the total quantity 1000 ml. This solution was filtered,sterilized and charged in ampoules with a content of 1 ml understerilized conditions to prepare an injection drug.

INDUSTRIAL APPLICABILITY

The compounds (I), salts thereof and their cyclodextrin inclusioncompounds according to this invention are safe compounds having bothaggressive factor inhibiting action and protective factor potentiationaction (cytoprotective effect). Antiulcer drugs containing them areuseful as preventive and curative medicines against both acute andchronic gastric ulcers, duodenal ulcers and gastric hyperacidities.

What is claimed is:
 1. A compound of the formula (I): ##STR41## in whichY is piperidino, 1-pyrrolidinyl, or 3-hydroxy-1-pyrrolidinyl, and Z is agroup selected from the group consisting of those having the formulas(a) to (e):(a) cyano; (b) a group of the formula ##STR42## in which lrepresents an integer from 0 to 2, n represents an integer from 1 to 3,R¹ is a hydroxy group, 1,2-dihydroxyethyl group, 1-hydroxyethyl group,2-phenoxy-1-hydroxyethyl group, 2-hydroxyethoxy group, loweralkoxycarbonyl group, 2,2-dimethyl-1,3-dioxolan-4-yl group, or a loweracyloxymethyl group; (c) a group of the formula ##STR43## in which R² isamino, lower alkylamino, di(2-hydroxyethyl)amino, lower alkyl, or loweralkoxy; (d) a group of the formula ##STR44## in which R³ and R⁴independently are hydrogen or lower alkyl; and (e) a group of theformula ##STR45## in which l represents an integer from 0 to 2, and R⁵and R⁶ independently are hydrogen or lower alkyl; or a salt orcyclodextrin inclusion compound thereof.
 2. An inclusion compound whichis obtained by including a compound of claim 1 in cyclodextrin.
 3. Anantiulcer composition comprising a pharmaceutically acceptable carrier,and as an active ingredient, a therapeutically effective amount of thesubstituted acetamide derivative or a salt thereof or a cyclodextrininclusion compound thereof as described in claim
 1. 4. A compound ofclaim 1, wherein Z is cyano.
 5. A compound of claim 1, wherein Z is##STR46## in which R² is amino, lower alkylamino,di(2-hydroxyethyl)amino, lower alkyl, or lower alkoxy.
 6. A compound ofclaim 1, wherein Z is ##STR47## in which R³ and R⁴ independently arehydrogen or lower alkyl.
 7. A compound of claim 1, wherein Z is##STR48## in which l represents an integer from 0 to 2, and R⁵ and R⁶independently are hydrogen or lower alkyl.
 8. A compound of the formula(I): ##STR49## in which Y is piperidino, 1-pyrrolidinyl, or3-hydroxy-1-pyrrolidinyl, and Z is ##STR50## in which l represents aninteger from 0 to 2, n represents an integer from 1 to 3, R¹ is hydroxy,1,2-dihydroxyethyl, 1-hydroxyethyl, 2-phenoxy-1-hydroxyethyl,2-hydroxyethoxy, lower alkoxycarbonyl, 2,2-dimethyl-1,3-dioxolan-4-yl,or lower acyloxymethyl; or a salt or cyclodextrin inclusion compoundthereof. 9.N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-hydroxyethyl-1-thio)acetamide.